The present invention relates to the use of IGF-I or analogues thereof in the manufacture of a medicament useful in the prevention and delaying the clinical onset of diabetes and having a protective effect against diabetes. The medicament is also useful in preventing beta cell destruction and regulating of T cells.
Insulin like growth factor-1 (IGF-1) and insulin are structural homologues, and elicit insulin-like and growth-promoting effects. In addition, IGF-1 has important effects on thymocyte replication and function independently of those of insulin. To evaluate the effect of IGF-1 on the autoimmune process of beta cell destruction, permissive recipients were adoptively transferred with T cells from diabetic donors and 10 xcexcg of rhlGF-1 were administered subcutaneously twice daily. The recipients of 7xc3x97106 autoreactive T cells were followed for clinical manifestations of diabetes and examined for in situ lesions after three weeks of treatment. We observed that the administration of rhlGF-1 delays the clinical onset of the disease and reduces the final incidence of successful transfers since diabetes was observed in only 6/24 (25%) vs 12/21 (57%) in control mice. These effects were associated with a marked reduction of insulitis. Mice treated with rhlGF-1 had a higher percentage of intact islets (48.6xc2x112% vs 1.6xc2x11.1%, p=0.001) and a lower percentage of infiltrated islets. However, some mice developed diabetes despite rhlGF-1 administration with severely infiltrated islets, indicating thus that committed T cells were still able to invade the islets and cause beta cell destruction. Three weeks after sub-lethal irradiation and T cell inoculation no difference was noticed in the percentages of CD4+ and CD8+ T cells in the spleen of experimental mice. To further elucidate whether rhlGF-1 could influence the homing of committed T cells, we adoptively transferred congenic NOD-N Thy-1,1 mice with T cells from diabetic NOD Thy-1,2 mice and monitored the numbers of Thy-1,2+ T cells present in lymphoid organs after three weeks of treatment. The administration of rhlGF-I was found to reduce significantly the percentage of Thy-1,2+ T cells in the spleen (10.8xc2x11.3% vs 17.2xc2x13.9%, p=0.004) in contrast to the thymus (68.4xc2x17.9% vs 72.87xc2x16.2, p=0,306). The findings that rhlGF-1 has protective effects and may act prior to islet cell invasion opens new perspectives for future experiments and preventive strategies in human type 1 diabetes.
The non-obese diabetes (NOD) mouse is an experimental model of spontaneous diabetes resembling human type 1 (insulin-dependent) diabetes, which results from the progressive islet invasion and beta cell destruction by autoreactive T cells (1,2). This spontaneous diabetes model offers a unique opportunity of studying the autoreactive T cells involved in the process of beta cell destruction and of settling preventive strategies before clinical onset of the disease. The number of committed T cells in the spleens of diabetic animals (3) and the respective contribution of T cell subsets (4) can be evaluated in vivo during adoptive T cell transfer into non diabetic syngeneic animals.
Insulin like growth factor-1 (IGF-1), a 70-amino acid peptide structurally related to insulin, is normally considered to be a metabolic hormone which mediates many effects of growth hormone. Prophylactic insulin treatment of NOD mice during the prediabetic phase (5) as well as insulin treatment of the NOD recipients of autoreactive T cells during adult T cell transfer (6) have been shown to prevent and/or delay the onset of diabetes and to reduce the severity of insulitis. Similar results have been also obtained in BB rats (7,8), which are another animal model of spontaneous autoimmune diabetes. Since insulin is a major antigenic component of the beta cells, it was not clear from these experiments whether insulin protective effects were explained by an antigen-specific unresponsiveness of the immune system, by a direct suppressive effect on T cell function, or by a direct effect on the beta cells.
The present study was undertaken to examine whether rhlGF-1 may have protective effects in the autoimmune diabetes of NOD mice using adoptive T cell transfer experiments.
The invention relates to the use of IGF-I or analogues thereof in the manufacture of a medicament useful in the prevention of diabetes and in delaying the clinical onset of diabetes.
IGF-I has also shown to have a protective effect against diabetes, in preventing beta cell destruction in subjects which are at high risk of development of diabetes and in the regulation of T cells in subjects which are at high risk of developing diabetes.
The invention relates to a method for treating patients having the above mentioned problems by administration of IGF-I or analogues thereof.
Possible daily dosages of IGF-I are 20 to 500 xcexcg/kg or preferably 20 to 250 xcexcg/kg or more preferably 100 to 200 xcexcg/kg.